Gastroprotective Effect and Cytotoxicity of Labdenamides

Abstract

Some 18 aromatic amides from the labdane diterpenes 15-acetoxyimbricatolic acid and 15-acetoxylabd-8(9)-en-19-oic acid were prepared and assessed for their gastroprotective effect in the HCl/EtOH-induced gastric lesion model in mice. The analysis of the gastroprotective activity of the benzylamides belonging to the series 8(9)- and 8(17)-ene was undertaken at doses of 12.5, 25 and 50 mg/kg in the HCl/EtOH-induced gastric lesion model in mice. A statistically significant gastroprotective effect was observed for 15-acetoxylabd-8(9)-en-19-oic acid benzylamide starting at 12.5 mg/kg, reducing the gastric lesions by 50%, while 15-acetoxylabd-8(17)-en-19-oic acid benzylamide reduced lesions by 66% at 25 mg/kg. The 25 mg/kg dose was used for the comparison of the different amides. At 25 mg/kg, the highest gastroprotective effect was observed for the benzyl- and 3-bromophenylamides from 15-acetoxyimbricatolic acid as well as for the benzyl- and P-toluidylamides of 15-acetoxylabd-8(9)-en-19-oic acid, being as active as lansoprazole at 20 mg/kg. Most compounds displayed low toxicity against epithelial gastric (AGS) and human lung fibroblasts cells, with IC50 values>1000 microM. The highest cytotoxicity towards AGS cells was observed for the 2-bromophenyl- and 2-hydroxy-5-chlorophenylamides in both diterpene series, with IC50 values in the range of 14-34 microM towards AGS cells and 10-37 microM towards fibroblasts, respectively.

Natural Products as Gastroprotective and Antiulcer Agents: Recent Developments

“…The triterpene saponins theasaponins A1 (60), A2 (61), F3 (62), assamsaponin A (63) and assamsaponin D (64), isolated from the seeds of Camellia sinensis, were tested for their gastroprotective effects. Theasaponin A2 (61) showed an inhibitory effect on ethanol-induced gastric mucosal lesions in rats at a dose of 5.0 mg/kg, p.o. and its activity was more potent than that of omeprazole.…”

New Gastroprotective Labdeneamides from (4S,9R,10R) Methyl 18-carboxy-labda-8,13(E)-diene-15-oate

“…The effect of the Mapuche crude drug Araucaria araucana resin on gastric lesions has been reported [6]. Several studies were undertaken to disclose the structure-activity relationships of labdane diterpenes from the resin as gastroprotective agents [13][14][15][16]. The effect of diterpene amide derivatives on the gastroprotective effect was reported for labdane [13,[15][16] and abietane [17] diterpenes.…”

“…PMD also differs from the Araucaria labdanes by the presence of an additional double bond at Δ13 (14). Diterpene amides from labdanes with aromatic amines [13] have shown good gastroprotective activity with lower basal cytotoxicity than the parent terpenes. The effect was higher than that elicited by amides with C-protected aminoacids [15,16].…”

Gastroprotective Mechanisms of Centipedic Acid, a Natural Diterpene from Egletes viscosa LESS.

“…7,8) Of particular interest of gastroprotective diterpenes are the clerodanes (trans-dehydrocrotonin from Croton cajucara, and aparisthman from Aparisthmium cordatum), the labdanes (solidagenone from Solidago chilensis and 15-acetoxylabd-8(17)-en-19-ol as well as 15,19-diacetoxylabd-8(17)-en from Araucaria araucana), abietane (ferruginol from Prumnopitys andin), and Jatrophone from Jatropha isabelli, 9,10) which may play a major role in drug discovery as well, in providing lead structures for the development of synthetic molecules. 11,12) In several parts of Brazil, tea or decoction prepared from the flower buds of Egletes viscosa (Asteraceae) is a popular remedy for the treatment of digestive and intestinal problems.13) Phytochemical studies on flower buds revealed the presence of diterpene compounds, centipedic acid (CPA) and 12-acetoxy-hawtriwaic acid lactone (tanabalin), and a tetramethoxy flavone, ternatin.14) Pharmacological investigations identified the anti-inflammatory, hepatoprotective, antidiarrhoeal and gastroprotective properties of ternatin. 15,16) In a previous study, we established the gastroprotective effects of both CPA and tanabolin against indomethacin and ethanolinduced gastric lesions, validating the traditional use of E. viscosa.…”

“…7,8) Of particular interest of gastroprotective diterpenes are the clerodanes (trans-dehydrocrotonin from Croton cajucara, and aparisthman from Aparisthmium cordatum), the labdanes (solidagenone from Solidago chilensis and 15-acetoxylabd-8(17)-en-19-ol as well as 15,19-diacetoxylabd-8(17)-en from Araucaria araucana), abietane (ferruginol from Prumnopitys andin), and Jatrophone from Jatropha isabelli, 9,10) which may play a major role in drug discovery as well, in providing lead structures for the development of synthetic molecules. 11,12) In several parts of Brazil, tea or decoction prepared from the flower buds of Egletes viscosa (Asteraceae) is a popular remedy for the treatment of digestive and intestinal problems.…”